JP7252967B2 - 連続検体測定のための生体適合性コーティング - Google Patents
連続検体測定のための生体適合性コーティング Download PDFInfo
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Description
本発明は、生体適合性層によって少なくとも部分的に覆われたセンサモジュールを含む検体を決定するためのバイオセンサであって、前記生体適合性層は、-CO-NR1R2側基(式中、R1及びR2は-H及びC1~C6アルキルから独立して選ばれる)を有するポリマーを含む、バイオセンサに関する。本発明はさらに、前記バイオセンサを製造するための方法ならびに前記バイオセンサに関連する使用及び使用方法に関する。
生体液中の検体を測定するためのバイオセンサ、特に埋め込み用に設計されたセンサは、様々な機能を発揮しなければならず、一方で、センサは、例えば、細胞などの体液の特定の化合物などから干渉されずに特定の敏感な測定を提供しなければならない。この目的のために、バイオセンサは、頻繁に、特定の化合物を排除する膜で覆われ、それにより、低分子量の化合物のみが実際のセンサモジュールにアクセスすることができる。さらに、埋め込まれたセンサでは、患者が頻繁にセンサを交換するのを避けるために、測定を悪化させることなく長期間にわたって適所に存続できるセンサが存在することが好ましい。したがって、埋め込まれたセンサは、身体が埋め込まれたセンサを認識して拒絶することを回避するために、生体適合性ポリマーで覆われる。さらに、適切な生体適合性層は、体液の成分がポリペプチド又は細胞などの膜上に堆積するのを防止すべきであり、堆積は膜の細孔の閉塞をもたらし、ノイズの増加及び測定の信号強度の低下を引き起こすからである。
したがって、本発明の目的は、特に汚染及びカプセル化プロセスに関する先行技術の欠点を少なくとも部分的に回避して、バイオセンサをコーティングするための改善された手段及び方法を提供することである。
この問題は、独立請求項の特徴を備えた本発明の手段及び方法によって解決される。独立した方法又は任意の組み合わせで実現できる好ましい実施形態は従属請求項に記載されている。
さらなる実施形態において、-CO-NR1R2側基を有するポリマーは、モノ-N-又はジ-N-置換アクリルアミドモノマー及び/又はO-置換メタクリレートモノマーのコポリマーである。さらなる実施形態において、ポリマーは、式(II)又は(IIa)
(a)本発明によるバイオセンサを前記対象の少なくとも1つの組織に埋め込むこと、及び、
(b)前記センサにより前記検体を決定すること、
を含む方法に関する。
(a)実施形態1~22のいずれか1項記載のバイオセンサを、前記対象の少なくとも1つの組織に埋め込むこと、及び、
(b)前記センサにより前記検体を決定すること、
を含む、方法。
図面の説明
p(BUMA/HEMA/HPMA):90:5:5のモル比を有するヒドロキシエチルメタクリレート、ヒドロキシプロピルメタクリレート及びブチルメタクリレートのコポリマー、PS:ポリスチレン、p(DMAA):97%のジメチルアクリルアミドと3%のベンゾフェノンメタクリレートのコポリマー、ラテックス:ACCUTech LOT 1307530704、リン酸緩衝生理食塩水(PBS)緩衝液(Lonzaにより入手可能なカルシウム又はマグネシウムを含まないDulbeccoのリン酸緩衝生理食塩水(BE17-512F);0.2g/lのKCl、0.2g/lのKH2PO4、8.0g/lのNaCl、2.16g/l Na2HPO4・7H2O)、滅菌生理食塩水溶液(SPSS)。
ポリマー層によるタンパク質吸着は、Q-Sense QSX301デバイスを使用した水晶振動子マイクロバランス(QCM)実験で研究した。これらの実験において、まずQCM基材(Q-Sense)をポリマー又はポリマーネットワークでコーティングした。コーティングされたサンプルを測定セルに入れ、振動させた。共振振動周波数を記録した。その後、サンプル表面をPBS緩衝液で覆い、ポリマーコーティングが平衡状態になるまで膨潤し始め、平衡状態により共鳴振動周波数は変化しなくなった。次に、振動周波数を再度記録し、緩衝液中の最終共振振動周波数を記録することにより、タンパク質吸着実験を開始した。約15分後、サンプルの表面を緩衝液でさらに覆い、タンパク質溶液を測定セルに添加し、サンプルの表面を約15分間覆い、その後、表面を緩衝液で再度洗浄して、付着していないタンパク質を除去した。サンプル表面上に吸着されたタンパク質は周波数の低下を引き起こし、この低下は吸着されたタンパク質の量と相関している。我々の実験において、p(BUMA/HEMA/HPMA)ポリマーをQCM基材表面に直接コーティングした。p(DMAA)ネットワークでの機能化のために、最初にポリスチレン層を基材にコーティングし、その上にp(DMAA)をスピンコーティングでコーティングし、次いで、UV照射によりネットワークとして固定化した。
細胞接着を基材としてのガラスカバーガラスで試験した。カバーガラスは石英ガラスからなり、直径1.5cmの円形を有した(VWR、ECN631-1579)。カバーガラスは、各実験工程の間に、コーティングを上向きにして、低発塵及び低細菌環境で24ウェルプレートに単独で保管した。カバーガラスを真空ピンセットで取り扱った。カバーガラスの表面を、スピンコーティングにより直接p(BUMA/HEMA/HPMA)でコーティングした。p(DMAA)コーティングの場合に、最初にカバーガラス表面をスピンコーティングによってポリスチレン(PS)でコーティングし、次にスピンコーティングによってp(DMAA)でコーティングし、その後再びUV照射した(365nm、0.35W/m2、2分)。コーティングを有しないカバーガラス及びPSのみのコーティングを有するカバーガラスを対照として使用した。
毒性試験のために、PET基材(2*2cm)の両面を、p(DMAA)でスピンコーティングし、次いでUV照射を行うことにより、p(DMAA)ネットワークでコーティングした。サンプルを使用前に電子線(25kGy)で滅菌した。3つの試験サンプルを4mLの細胞培養培地に37℃で24時間浸した。インキュベートした細胞培養培地(溶出液)1mLを新しい96ウェルプレートのウェルに移し、L929線維芽細胞を加えてさらに24時間インキュベートし、その後に、細胞の生存率をXTT-テストを使用して測定した。結果は、基準(例えば100%)として未処理の細胞培養培地を使用して、%細胞増殖として示す。したがって、%増殖値が低いほど、細胞内のサンプルの毒性効果が強くなる。ラテックス手袋から切断された断片及びp(BUMA/HEMA/HPMA)でコーティングされたPET基材から上記のように調製された溶出液を対照として使用した。例えば、ラテックス手袋から切り取った断片を陽性対照として使用し、コーティングを有しないPET基材を陰性対照として使用した。図3に示すように、p(DMAA)コーティングはL929細胞上で検出可能な毒性を示さなかった。
ポリマーの炎症誘発可能性を試験するために、ヒト細胞株THP-1を使用した。THP-1細胞は単球様細胞であり、外因性の刺激によって活性化されることができ、該刺激は細胞に培養培地へのサイトカインの分泌を増加させる。この活性化は、誘導材料との表面接触によって直接、又は、材料から放出された可溶性成分によって誘導することができる。さらなる選択肢は、ポリマーの表面との接触により活性化されるフィブリノーゲンによる細胞の活性化である。フィブリノーゲンのこの活性化は、構造の変化を引き起こし、THP-1細胞上の免疫受容体に結合する結合部位を露出させ、それによって細胞の活性化を引き起こす。さらに別の選択肢は、フィブリノーゲン吸着によるコーティング表面上の細胞の活性化である。この表面付着は、フィブリノーゲンの構造変化を引き起こし、それを介して結合部位が露出し、THP-1細胞上の免疫受容体に結合することができ、それによって細胞の活性化が引き起こされる。
US 2006/0198864 A1
EP 0 821 234
EP 0 974 303
US 2005/0023152
US 5,385,846
US 5,997,817
US 10/008,788
WO 2007/012494
WO 2009/103540
WO 2011/012269
WO 2011/012270
WO 2011/012271
EP 0 354 441
EP 0 431 456
WO 2015/005953 A1
J. Hoenes ら: The Technology Behind Glucose Meters:Test Strips, Diabetes Technology&Therapeutics, Volume 10, Supplement 1, 2008, S-10~S-26。
Claims (16)
- R1及びR2は-H及びC1~C3アルキルから独立して選ばれる、請求項1記載のバイオセンサ。
- R 1 及びR 2 はメチル、-H及びエチルから独立して選ばれる、請求項1記載のバイオセンサ。
- R 1 及びR 2 はメチルである、請求項1記載のバイオセンサ。
- -CO-NR1R2側基を有する前記ポリマーはコポリマーである、請求項1~4のいずれか1項記載のバイオセンサ。
- -CO-NR 1 R 2 側基を有する前記ポリマーは統計コポリマーである、請求項1~5のいずれか1項記載のバイオセンサ。
- nは0.5~0.99であり、mは0.01~0.5であり、mとnの合計は1である、請求項1~6のいずれか1項記載のバイオセンサ。
- 拡散膜をさらに含み、前記拡散膜は親水性ポリウレタンポリマーを含む、請求項1~7のいずれか1項記載のバイオセンサ。
- 前記バイオセンサは、皮下にインプラント可能である、請求項1~8のいずれか1項記載のバイオセンサ。
- 前記検体は、グルコース、マレート、エタノール、アスコルビン酸、コレステロール、グリセロール、尿素、3-ヒドロキシブチレート、ラクテート、ピルベート、ケトン及びクレアチニンからなるリストから選ばれる、請求項1~9のいずれか1項記載のバイオセンサ。
- 前記検体は、グルコースである、請求項1~9のいずれか1項記載のバイオセンサ。
- 前記検体の決定は連続グルコースモニタリングである、請求項1~9のいずれか1項記載のバイオセンサ。
- 検体を決定するためのインプラント可能なバイオセンサを製造するための方法であって、請求項1~7のいずれか1項に特定された生体適合性層で前記バイオセンサを少なくとも部分的にコーティングすることを含む、方法。
- インプラント可能なバイオセンサを製造するための、請求項1~7のいずれか1項に特定された生体適合性層の使用。
- 対象における検体の連続決定のための方法であって、前記方法は請求項1~12のいずれか1項記載のバイオセンサによって前記検体を決定することを含む、方法。
- 前記連続決定は、同じバイオセンサを使用した、少なくとも1週間、少なくとも2週間、少なくとも3週間、又は少なくとも4週間の決定である、請求項15記載の方法。
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